Over 4 million babies are born each year in the United States, and each one is contaminated with a variety of industrial chemicals including polychlorinated biphenyls (PCBs). PCB production was banned in the 1970s after over a billion kilograms were produced, but over 60% of this material remains in use today. PCB body burden of pregnant women is associated with deficits in cognitive function and with structural differences in the brain of their offspring. A leading theory is that some PCBs can cause a reduction in circulating levels of thyroid hormone (TH), thereby damaging brain development. We have demonstrated in animal studies that PCBs can also interfere with TH action at the receptor (TR) independent of circulating levels of TH. Moreover, we have shown in vitro that this action is restricted to a specific hydroxylated PCB metabolite, and in previous and current animal work we extend this observation to the whole animal and find tissue-specific variability in the effect of PCB exposure on TH signaling. This is important because this metabolite, 4-OH-PCB107, is uniquely and negatively correlated with measures of cognitive function. This ViCTER mechanism provides a rare opportunity to translate our work directly into developing human tissues. Therefore, to enhance the aims of the parent grant, we propose two new aims in collaboration with Dr. Tracey Woodruff (UCSF) and Dr. Martin Privalsky (UC Davis). In the first aim, we will test whether 4-OH- PCB107 in human fetal liver is correlated with the levels of expression of thyroid hormone response genes in this tissue. To interpret our findings, we will also use microarray analysis of the effects of 4- OH-PCB107 on primary fetal hepatocytes. In the second aim, we will evaluate the molecular mechanisms by which 4-OH-PCB107 interacts with the thyroid hormone receptor. The proposed studies will be first-of-a-kind that directly tests whether PCB metabolites can directly interfere with thyroid hormone signaling in the human fetus. These studies have the potential to change the way we think about "thyroid toxicants" and the approaches we use to study chemical impacts on thyroid hormone-regulated development in human populations. In addition, we will have direct measurements of the role of PCBs in inducing liver enzymes to increase xenobiotic metabolism, adding to our understanding of whether the fetus may be a sink for environmental contaminants. Because of the highly integrated nature of this work, requiring efforts from all three labs for successful completion of the work, we are proposing only 2 aims and designate the part of the work that is performed in each lab.